In order to understand the role of met-enkephalin in neurotransmission and the possible involvement of this endogenous peptide in psychiatric disorders, we have studied the effect of some psychotropic drugs on the (met5)-enkephalin content in various brain regions. Chronic treatment with haloperidol, pimozide, chlorpormazine and clozapine, antipsychotics endowed with dopaminergic receptor blocking activity, led to a marked elevation of the enkephalin content in striatum and nucleus accumbens suggesting an interaction between enkephalinergic and dopaminergic neurons in these two regions. Increase of (met5)-enkephalin content in striatum and nucleus accumbens was also observed in the rats chronically treated with lithium. In order to analyze the role of enkephalin in mediating the effect of these drugs, an attempt was made to study the turnover rate and the biosynthesis of met-enkephalin in brain. The turnover rate of met-enkephalin in brain is slow and the incorporation of radioactive amino acids into enkephalins is made difficult by the presence of large pools of precursors. Two endorphin-like peptides with molecular weight larger than met-enkephalin were detected in bovine caudate and they are neither beta-lipotropin or alpha or beta-endorphin. These two peptides are being studied for their role as possible precursors of meta5)-enkephalin.